The alkaloid epibatidine was first isolated in 1974 from the skin of the Ecuadorian frog Epipedobates tricolor. Shortly afterwards, its analgesic potency was shown to be about 200-fold higher than that of morphine. Regrettably however, the toxicity of epibatidine is too high for any human therapeutic use. The mode of action of epibatidine was later revealed as a highly potent nicotinic acetylcholine receptor agonist. This membrane bound pentameric ion channel has been associated with many neurological disorders such as Alzheimer disease, Parkinson disease and schizophrenia. For each of these disorders, there is a shift in the prevalence of the different nicotinic actylcholine receptor subtypes.
In order to improve the ratio of pharmacological to toxicological activity, many analogues have been synthesized. Most of them are substituted at position 2 of the 7-azabicyclo-[2.2.1]heptyl ring, e.g. WO 00/23424, U.S. Pat. Nos. 6,060,473, 5,817,679, 6,117,889, 6,077,846, 5,510,490, EP 657,455, U.S. Pat. No. 6,562,816, and EP 955,301. Grygorenko et al in Tetrahedron (2006) 17:252 has also disclosed one derivative substituted at position 1 of the 7-azabicyclo-[2.2.1]heptyl ring, i.e. 7-(1-phenylethyl)-7-azabicyclo-[2.2.1]heptyl-1-carbonitrile. However there is still a need in the art for more subtype selective epibatidine analogues in an effort to provide treatment for neurological diseases such as, but not limited to, Alzheimer disease, Parkinson disease and schizophrenia.